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Biomedical subjects

W Havers

Publications and source records attributed to W Havers.

At least 19 recordsLinked to original sources
PubMed2003

High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma.

Children with metastatic retinoblastoma are considered to have a poor prognosis after conventional chemotherapy. We used high-dose chemotherapy (HDC) with peripheral hematopoietic stem cell transplantation in such patients in an attempt to improve their survival. Four patients with bone marrow metastases and one child with extraorbital disease were treated with HDC after achieving complete remission by enucleation and conventional chemotherapy. The child with extraorbital tumor was the only one to receive local irradiation. The conditioning regimen included thiotepa (900 mg/m(2)), etoposide (40 mg/kg) and carboplatin (1.5 g/m(2)) in four patients, and BCNU (300 mg/m(2)), cyclophosphamide (6.8 g/m(2)) and etoposide (1.6 g/m(2)) in one child. Hematologic recovery occurred without delay in all patients. The main toxicities were diarrhea, mucositis and infectious complications. No toxic deaths or any major late toxicities were observed. The child treated with the BCNU regimen developed a meningeal relapse 10 months after HDC, which was partially resected and treated with conventional chemotherapy, but not with radiotherapy. He is in complete remission (CR) 105 months off treatment. The other patients are in CCR for 107, 57, 9 and 8 months after HDC. HDC with thiotepa, etoposide and carboplatin may represent a curative option for children with extrabulbar or disseminated retinoblastoma responsive to chemotherapy. It may control occult CNS disease. The necessity to irradiate these children and the curative potential of this strategy for patients with bulky CNS disease remain to be determined.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Thermochemotherapy in hereditary retinoblastoma.

BACKGROUND/AIM: The combination of chemotherapy and transpupillary thermotherapy, thermochemotherapy (TCT) has become an established part of the treatment plan in advanced retinoblastoma. The aim of this study was to identify safe indications, the complications as well as the limitations of this new treatment for retinoblastoma. METHODS: Tumour response and side effects of TCT with an indirect laser ophthalmoscope (spot size about 400 micro m) in 55 tumours of 26 children with bilateral retinoblastoma were analysed. Using the Reese-Ellsworth classification system, nine of 35 eyes were classified as type I, 13 eyes as type II, 10 eyes as type III, and three eyes as type V. The mean age of the children was 0.74 (SD 0.61) years. The mean tumour height was 3.5 (2.3) mm with a mean diameter of 6.1 (4.1) mm. Treatment parameters were 4.3 (1.6) (median 5) thermochemotherapy sessions with a mean energy of 539 (211) mW and a mean duration of 13.5 (5.6) minutes. Chemotherapy courses (vincristine, etoposide, and carboplatin) were repeated every 3 weeks. The mean follow up period was 1.25 (0.6) years. RESULTS: Local recurrence occurred in 21 tumours (38%), with a mean onset of 3.2 (2.9) months after TCT. The risk of tumour recurrence was correlated with tumour height. The recurrence rate was 17% for tumours with a height less than 2 mm, 37% for tumours with a height between 2 and 4 mm, and 63% for larger retinoblastomas. Multivariate analysis identified fish flesh regression after TCT (p = 0.0007) as the most important risk factor for tumour recurrence besides tumour height (p = 0.001) and the necessity of increased laser power during TCT sessions (p = 0.018). Complications during therapy included transient corneal opacification in two eyes (6%), focal iris atrophy (three eyes, 8.5%), peripheral lens opacity (two eyes, 6%), circumscribed transient retinal detachment (one eye, 3%) and diffuse choroidal atrophy (one eye, 3%). CONCLUSION: TCT using an indirect laser ophthalmoscope with a spot size of about 400 micro m was efficient for retinoblastoma with a tumour height less than 4 mm. In larger tumours, the recurrence rate was unacceptably high. Fish flesh regression after TCT correlates with a higher rate of local tumour recurrence. Treatment related complications occurred in less than 9% of the treated eyes.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Allogeneic CD34+ -selected peripheral stem cell transplantation from parental donors in children with non-malignant diseases.

Allogeneic peripheral stem cell transplantation in six children with non-malignant hematologic or metabolic diseases which are eventually fatal was carried out with parental donors. Given three to five HLA mismatches, all grafts underwent CD34+ cell selection as graft-versus-host prophylaxis. The patients received median doses of 16.7 x 10(6) CD34+ cells/kg and 1.2 x 10(4) CD3+ cells/kg. All transplants engrafted. Neutrophils >0.5/nl were reached on day 11 (9-19) and platelets >50/nl on day 13 (10-25). Acute GVHD responding to steriods occured in three of six patients; it was restricted to the skin and overall did not exceed grade I. Two patients died of viral infections and four are alive with stable blood counts for 13, 15, 25 and 26 months. For children with non-malignant diseases which will eventually be fatal and which can be cured or ameliorated by allogeneic BMT, CD34+-selected stem cell transplants from mismatched or even haploidentical parents can be used if no other suitable donor is available. With high CD34+ cell doses and low CD3+ cell numbers, engraftment and avoidance of acute GVHD can be expected. Infections after transplantation remain the primary threat to survival.

Acute Disease↗
PubMed2001

Quantification of angiogenesis stimulators in children with solid malignancies.

Humoral angiogenesis stimulators including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been implicated in the pathogenesis of solid malignancies. However, it has remained unclear whether both stimulators contribute to the development and progression of solid malignancies of children. The aim of the present study was to determine whether VEGF and bFGF are elevated in body fluids of children with solid malignancies and, if so, whether these elevated levels correlate with clinical parameters. Using enzyme-linked immunosorbent assays (ELISAs), we quantified VEGF and bFGF in serum (n = 107) and urine (n = 57) of healthy children and of children with solid malignancies (serum: n(VEGF) = 69, n(bFGF) = 60; urine: n(VEGF) or n(bFGF) = 13). Finally, we compared patients' pre-therapeutic and post-therapeutic levels. Serum VEGF was elevated in children with several solid tumors (Ewing's sarcoma, primitive neuroectodermal tumours, malignant lymphoma, Langerhans cell histiocytosis and medulloblastoma). In contrast, serum bFGF, urinary bFGF or urinary VEGF were not significantly elevated. Upon successful therapy, elevated pre-therapeutic serum VEGF levels declined to levels present in healthy children. VEGF could contribute to the progression of pediatric solid malignancies, and serum VEGF could be used to monitor therapeutic response. Furthermore, the determination of angiogenesis stimulators could identify patients eligible for anti-angiogenic therapy.

Adolescent↗
PubMed2001

Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster 93.

PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) 87. RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P =.01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P =.007; and 44% v 31%, P =.01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.

Adolescent↗
PubMed2001

Hypoxia promotes apoptosis of human neuroblastoma cell lines with enhanced N-myc expression.

We have examined the effect of hypoxia and nutrient depletion on the growth of human neuroblastoma cells with normal or enhanced expression of the N-myc oncogene. The combination of both conditions reduced the growth of neuroblastoma cells with normal N-myc expression. However, this effect was much more pronounced in neuroblastoma cells with enhanced N-myc expression and eventually resulted in apoptosis, presumably by the up-regulation of CD95. Our data suggest that therapeutic induction of tumor hypoxia and nutrient depletion (for example, by anti-angiogenesis) could help to improve the outcome of patients with neuroblastomas carrying the prognostically unfavourable N-myc amplification.

Apoptosis↗
PubMed2001

Primary B-cell lymphoma of bone in children.

UNLABELLED: Primary lymphoma of bone (PLB) is a rare entity of extranodal non-Hodgkin lymphoma (NHL). We report on two children with PLB focussing on diagnostic evaluation and treatment strategy. Clinical and radiographic presentation in both children suggested a primary bone tumour such as Ewing sarcoma. A 13-year-old girl showed osteolytic tumours in the right 7th rib and right iliac crest. Additional skeletal lesions were found by whole-body positron emission tomography. A 6-year-old boy presented with an isolated, osteolytic lesion of the left distal femur. In both patients staging procedures excluded any organ involvement besides the skeletal tumours. Tumour biopsy and immunohistological studies revealed lymphoblastic non-Hodgkin lymphoma of B-cell lineage in both children. They received a polychemotherapy for B-cell lymphoma according to the NHL-BFM 95 protocol and are in complete remission with a follow up of 24 and 18 months respectively. CONCLUSION: Isolated, primary lymphoma of bone in children may clinically and radiographically impose as primary bone tumour. Multiple therapeutic strategies have been applied in the treatment of this malignancy, however, treatment modalities are not well focussed on immunological patterns in the case of primary lymphoma of bone. Staging techniques should include immunophenotyping to initiate specific cell lineage treatment.

Adolescent↗
PubMed2001

Piperacillin, beta-lactam inhibitor plus gentamicin as empirical therapy of a sequential regimen in febrile neutropenia of pediatric cancer patients.

The beta-lactam/beta-lactamase inhibitor combinations are a good choice for empirical antimicrobial therapy in febrile neutropenic patients, because their antibacterial spectra include both gram-negative and gram-positive pathogens. This trial was initiated to assess the efficacy and safety of piperacillin with the beta-lactam inhibitors sulbactam (PSG group) or tazobactam (PTG group) and gentamicin as initial therapy in febrile neutropenia of pediatric patients. In a prospective study, 239 episodes of fever and neutropenia were analyzed for the clinical and microbiological response dependent on infection etiology and treatment group: 66.5% of episodes were classified as fever of unknown origin (FUO) and 33.5%, as microbiologically or clinically documented infections; 19.2% of all episodes were due to bacteremia, predominantly caused by gram-positive organisms (69.6%). The response to the initial therapy was 55.2% overall and 65.4% in episodes of FUO with a significant higher success rate in the PSG group than in the PTG group (70.1% vs. 52.4%, P=0.039), and 35.0% in documented infections. In episodes with documented infection longer duration of fever and antimicrobial therapy was recorded than for FUO episodes. Four patients died of causes related to infection. Fever relapse occurred in 26 episodes (11.1%), predominantly in patients who were still neutropenic. Toxic side effects were minimal. The initial therapy of piperacillin with sulbactam or tazobactam in combination with gentamicin is well tolerated, and its efficacy is comparable to that of other combination therapies or of monotherapy with beta-lactam antibiotics in pediatric neutropenic cancer patients.

Adolescent↗
PubMed2001

Multiple angiogenesis stimulators in a single malignancy: implications for anti-angiogenic tumour therapy.

Anti-angiogenesis is likely to develop into a novel therapeutic approach for patients with solid malignancies. Most current clinical trials evaluate anti-angiogenic drugs aimed primarily against single angiogenesis stimulators. Here, we show that a single solid malignancy, i.e., a human embryonal rhabdomyosarcoma, produces in vivo at least three biologically active angiogenesis stimulators (vascular endothelial growth factor, basic fibroblast growth factor and interleukin-8). This suggests that tumour angiogenesis results from the activity of multiple, rather than a single angiogenesis stimulator(s). We, furthermore, show that a combination of anti-angiogenic drugs is more effective in inhibiting tumour-induced endothelial cell growth than a single agent. Our results imply that clinical anti-angiogenic strategies for the treatment of solid malignancies may be most effective when multiple rather than single antiangiogenic drugs are used.

Angiogenesis Inhibitors↗
PubMed2001

Transplantation of CD34-enriched peripheral stem cells from an HLA-haplotype mismatched donor to a patient with severe aplastic anemia.

A 14-year-old girl developed very severe aplastic anemia unresponsive to steroids, cyclosporine, ATG and filgrastim. She experienced repeated bacterial infections, hypermenorrhagia and epistaxis and received numerous transfusions. Lacking a matched family or unrelated donor, she was transplanted 6 months after diagnosis with CD34+ cell-enriched peripheral stem cells from her HLA-haploidentical uncle. Conditioning included fludarabine, cyclophosphamide, 800 cGy TLI and OKT3. Prompt and sustained trilineage engraftment occurred. Acute GVHD grade 1 and herpes esophagitis were successfully treated. Eight months after grafting she was well with stable hematopoiesis. She then succumbed to fulminant hepatic failure due to adenovirus infection.

Adenoviridae Infections↗
PubMed2001

Meropenem versus ceftazidime as empirical monotherapy in febrile neutropenia of paediatric patients with cancer.

This trial assessed the efficacy and safety of meropenem versus ceftazidime as empirical monotherapy for febrile neutropenia in paediatric cancer patients. In a prospective randomized study, 172 evaluable febrile episodes in the meropenem arm and 170 episodes in the ceftazidime arm were analysed for the clinical and microbiological response dependent on the kind of infection. About half the episodes were classified as fever of unknown origin (FUO) and the remainder as microbiologically or clinically documented infections. The most frequently documented infections in both arms were bacteraemias (22.1 versus 26.5%), predominantly caused by Gram-positive organisms (57.9 versus 71.1%). The success rate of the initial monotherapy differed significantly between the two arms and was 55.8% in the meropenem and 40.0% in the ceftazidime arm (P = 0.003). In addition, a significantly longer duration of fever and of antimicrobial therapy was observed in the ceftazidime arm than in the meropenem arm (median 5 versus 4 days, P = 0.022, and 7 versus 6 days, P = 0.009, respectively). With respect to the kind of infection, differences between the two arms were significant only in episodes classified as FUO but not in documented infections. In both arms, side effects were minimal. Despite the greater response rate for meropenem in FUO, the fact that ceftazidime has been proven to be as effective as meropenem in documented infections in the present study suggests that both drugs are useful as empirical monotherapy in febrile paediatric cancer patients.

Bacterial Infections↗
PubMed2000

Transplant activities in Germany in 1998--a survey facilitated by the National Registry for Hemopoietic Stem Cell Transplantation.

To improve the infrastructure of hemopoietic stem-cell transplantations in our country, the German Registry for Hemopoietic Stem-Cell Transplantations (DRST) was established in 1998. The present paper summarizes the current status of the DRST and gives a survey of transplant activities in Germany in 1998 in terms of transplant units, transplant types, transplant frequencies and underlying diseases.

Blood Cells↗
PubMed2000

Arginine deiminase inhibits proliferation of human leukemia cells more potently than asparaginase by inducing cell cycle arrest and apoptosis.

L-Asparaginase is used for the treatment of acute leukemias, but is sometimes ineffective or associated with severe side-effects. We report here that the enzyme arginine deiminase is approximately 100-fold more potent than L-asparaginase in inhibiting the proliferation of cultured human lymphatic leukemia cell lines while it appears to be less effective in leukemia cells of myeloid origin. The inhibition of cell proliferation involves cell growth arrest in the G1- and/or S-phase and eventually apoptotic cell death. Our results suggest the possibility of a future use of arginine deiminase for the therapy of leukemia.

Antineoplastic Agents↗
PubMed2000

Haematopoietic stem cell transplantation for amegakaryocytic thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAT), a rare syndrome with failure of megakaryopoiesis, cannot be cured by immunoglobulins, steroids or cyclosporin, but only by allogeneic bone marrow transplantation (BMT). We report on eight patients with CAT, all of whom were dependent at the time of BMT on platelet transfusion. Sources of haematopoietic progenitor cells were bone marrow (n = 5), peripheral stem cells (n = 2) and cord blood (n = 1). Seven patients engrafted. Both patients with matched unrelated donor transplants died, six patients are well with stable platelet counts 3-27 months after transplantation. BMT represents a curative option for CAT. The benefit of using alternative marrow donors should be carefully evaluated.

Bone Marrow Cells↗
PubMed1999

Arginine deiminase inhibits cell proliferation by arresting cell cycle and inducing apoptosis.

We have previously demonstrated that arginine deiminase inhibits the proliferation of vascular endothelial cells, but the mechanisms leading to growth inhibition have remained unclear. We report here that low concentrations of arginine deiminase purified from Mycoplasma arginini inhibit proliferation of various cultured cells by arresting the cell cycle in G(1) and/or S phase with higher arginine deiminase concentrations leading to subsequent apoptosis. Our results demonstrate that arginine deiminase inhibits cell proliferation not only by depletion of arginine, but also by mechanisms involving the cell cycle and death signals.

Apoptosis↗
PubMed1999

Vascular endothelial growth factor expression in human neuroblastoma: up-regulation by hypoxia.

Enhanced angiogenesis apparently contributes to the poor clinical outcome of human neuroblastoma, but the mechanisms have remained unclear. We report here that cultured human neuroblastoma cells express a bioactive endothelial cell growth factor indistinguishable from the angiogenesis stimulator vascular endothelial growth factor (VEGF). VEGF is present in neuroblastoma but not vascular endothelial cells, whereas the corresponding VEGF receptors (Flt-1 and Flk-1/KDR) are expressed in endothelial but not neuroblastoma cells. Exposure of neuroblastoma cells to hypoxia induces a marked increase in bioactive VEGF. VEGF is also present in human neuroblastoma specimens, with substantial amounts in apparently hypoxic neuroblastoma cells, eventually accumulating in tumor microvessels. Our results indicate that VEGF (i) is present in human neuroblastomas, (ii) is up-regulated by tumor hypoxia and (iii) may stimulate neuroblastoma angiogenesis by paracrine mechanisms, thereby contributing to the progression of human neuroblastomas. We suggest that inhibition of VEGF activity may represent a novel approach for the therapy of human neuroblastoma.

Cell Division↗